Quinoline derivatives

ABSTRACT

The invention provides a compound of formula III ##STR1## or an acid addition salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are the same or different and represent hydrogen or lower alkyl, cycloalkyl, lower aralkyl or phenyl radicals any of which radicals may be substituted by lower alkyl, lower alkoxy or trifluoromethyl or R 2  and R 3  taken together, form a 5, 6 or 7 membered saturated ring, R 4  and R 5  may also represent lower alkoxy or cycloalkoxy, n is 1, 2 or 3 and, if more than one R 4  radical is present the R 4  radicals may be the same or different and esters of carboxylic acids with the hydroxy group shown, wherein R 1 , R 2 , R 3 , R 4 , R 5  and n are as defined above, with the provisos that (1) R 6  and R 7  are other than hydrogen when R 1 , R 2 , R 3 , R 4  and R 5  are all hydrogen and (2) R 6  and R 7   are not both methyl when R 4  is methyl. 
     Compounds III are intermediates for other compounds with anti-ulcer or anti-secretory activity. Some of the compounds III are intermediates for anti-inflammatory agents.

The invention relates to quinoline derivatives and is acontinuation-in-part of our copending U.S. Ser. No. 571 972 filed 18Jan. 1984, now U.S. Pat. No. 4,837,329.

In our copending U.S. Ser. No. 571972 we have disclosed a process forpreparing dihydro compounds of formula I ##STR2## and acid additionsalts thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same ordifferent and represent hydrogen, or alkyl, cycloalkyl, aralkyl, or arylradicals any of which radicals may by substituted, or R¹ and R² takentogether or R² and R³ taken together, form a 5, 6 or 7 membered ringwhich may be saturated or unsaturated and substituted or unsubstituted,R⁴ and R⁵ may also represent alkoxy, or cycloalkoxy, n is 1, 2 or 3 and,if more than one R⁴ radical is present the R⁴ radicals may be the sameor different which process comprises re-arranging a compound of formulaII ##STR3## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and n are as definedabove.

The re-arrangement of compound II to compound I may be carried out underacidic or basic conditions. Examples of acid catalysts which may be usedare organic acids such as carboxylic acids e.g. lower alkylcarboxylicacids such as acetic acid, inorganic acids such as phosphoric acid, orpolyphosphoric acids, Lewis acids e.g. boron trifluoride, zinc chlorideor acid anhydrides e.g. acetic anhydride. Alternatively a noble metalcatalyst, e.g. a Pt or Pd catalyst may be used, optionally in thepresence of a weak base such as sodium acetate or a heterogeneous orhomogeneous catalyst, e.g. PdCl₂ (PhCN)₂, RhCl[(C₆ H₅)₃ P]₃ Ru₃ (CO)₁₂or IrCl(CO)[(C₆ H₅)₃ P]₂

Preferably the rearrangement is carried out in the presence of aceticacid, a noble metal catalyst in the presence of a base, or a Lewis acid.

The above mentioned acids may be used to prepare acid addition salts ofcompounds of formula I and other compounds of the invention.

When any of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ is an alkyl radical it ispreferred that this is a lower alkyl radical of 1 to 6 carbon atomswhich may have a straight or branched chain e.g. methyl, ethyl, n- andiso-propyl and n-, s- and t-butyl. When R⁴ or R⁵ is an alkoxy radical itis preferred that the radical is lower alkoxy in which the alkyl portionhas 1 to 6 carbon atoms and is as defined above, for an alkyl radical.

When any of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ is a cyclo-alkyl radical suchradicals having from 4 to 6 carbon atoms are preferred i.e. cyclobutyl,cyclopentyl or cyclohexyl. If R⁴ or R⁵ is cycloalkoxy the cycloalkylportion of this group may be as just described for a cycloalkyl group.An aralkyl group may be an arylalkyl group in which the alkyl portion isas described herein for an alkyl group. Preferred aralkyl groups arethose having from 7-12 carbon atoms.

When any of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ is an aryl group it ispreferably phenyl or substituted phenyl (substituted by e.g. alkyl,alkoxy or trifluoromethyl). The aryl portion of an aralkyl group may besubstituted as described for a phenyl group.

The present invention concerns intermediates for compounds of formulaII, which intermediates have formula III.

The starting materials of formula II may be prepared by dehydration ofthe corresponding compounds of formula III ##STR4## wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and n are as defined above.

The dehydration may be carried out with usual dehydration agents e.g.polyphosporic acid or with acetic anhydride, (in which case anintermediate acetylated derivative may be formed, from which acetic acidis eliminated to give the compound of formula II).

Some compounds of formula III are novel and are included in theinvention. These are compounds of formula III and their acid additionsalts and esters of carboxylic acids wherein R¹, R², R³, R⁴, R⁵ and nare as defined above in connection with formula I and R⁶ and R⁷ areother than hydrogen when R¹, R², R³, R⁴, and R⁵ are all hydrogen and R⁶and R⁷ are not both methyl when R⁴ is methyl.

Preferred compounds of formula III are the sub group of formula IIIA##STR5## or an acid addition salt thereof wherein R¹⁰ is lower alkyl andR⁶ and R⁷ are selected from hydrogen, lower alkyl, cycloalkyl, or loweraralkyl radicals. Examples are[8R*]-5,6,7,8,-tetrahydro-8-([2S*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline;5,6,7,8-tetrahydro-8-(2-(2-hydroxy)propyl-3-methylquinoline and theiracid addition salts.

The compounds of formula III may be prepared by treatment of a compoundof formula IV ##STR6## wherein R¹, R², R³, R⁴, R⁵ and n are as definedin connection with formula I, and M is hydrogen, an alkali metal (e.g.sodium, potassium or lithium) or MgHal, where Hal is chlorine, bromineor iodine, with a carbonyl compound of formula V ##STR7## wherein R⁶ andR⁷ are as defined in connection with formula I, with the proviso thatwhen R⁶ and R⁷ are both hyrogen then M is hydrogen.

It has been reported by Hahn and Epsztajn, Roczniki Chemie, 1964, 38,989 that treatment of VIa or VIb ##STR8## with polyphosphoric acid givesthe corresponding methylene compounds VIIa and VIIb ##STR9## exclusivelywith no corresponding methyl isomer being formed. We have surprisinglyfound that compounds of formula I wherein R⁶ and R⁷ are hydrogen, can beobtained by treatment of a compound of formula IV wherein M is hydrogenwith formaldehyde (which may be in the form of paraformaldehyde) in thepresence of an organic acid anhydride, e.g. acetic anhydride. It isbelieved that an intermediate compound of formula III wherein R⁶ and R⁷are both hydrogen is formed initially, this dehydrates to give acompound of formula II wherein R⁶ and R⁷ are hydrogen and the compoundof formula II rearranges to give a compound of formula I wherein R⁶ andR⁷ are hydrogen.

Previously compounds of formula I were relatively inaccessible--seeRosen and Weber J Org. Chem. 1977, 42, 47-50 who obtained8-methyl-5,6-dihydroquinoline by pyrolysis of1-methyl-1(α-pyridinyl)-1,3-butadiene. However pyrolysis is not asatisfactory method of preparation especially for molecules carrying avariety of substituents.

Compounds of formula I may be used as intermediates for the preparationof the corresponding compounds of formula XIV ##STR10##

Compounds of formula XIV are intermediates for other compounds withanti-ulcer or anti-secretory activity e.g. the compounds of UK PatentSpecification No. 1432378. Some compounds of formula II where R⁶ and/orR⁷ are phenyl or substituted phenyl may also possess anti-inflammatoryactivity as determined by standard test procedures.

The invention is illustrated by the following Examples.

EXAMPLE 1 3,8-Dimethyl-5,6,7,8-tetrahydroquinoline

A mixture of 3-methyl-5,6,7,8-tetrahydroquinoline (100 ml)paraformaldehyde (30 g) and acetic anhydride (100 ml) was heated atreflux for 30 hours. The residue was distilled to give a mixture ofstarting tetrahydroquinoline and 3,8-dimethyl-5,6-dihydroquinoline (40g) bp. 126°-180°/15 mm. Chromatography on silica gel (500 g, Woelmactive, 100-200) using di-isopropyl ether gave3,8-dimethyl-5,6-dihydroquinoline (22 g).

A solution of the dihydroquinoline (22 g) in ethanol (200 ml.) washydrogenated over 10% palladium on carbon (1 g) at 25° and 1 atmosphere.After the theoretical uptake had occurred (1.5 hours) the catalyst wasremoved by filtration, the filtrate evaporated and the residue distilledto give the title tetrahydroquinoline (22 g) bp. 124°/15 mm C₁₁ H₁₅ Nrequires: C, 81.9; H, 9.4; N, 8.7%. Found: C, 81.9, H, 9.1, N, 8.3%

The catalyst in this example is a mixture of acetic anhydride and aceticacid, the acetic acid being produced in situ.

EXAMPLE 2 Compound Present

The reaction described in Example 1, 1st paragraph, was followed in atime course experiment, samples being taken at intervals and compositionanalysed by glc. (Pye 104 C20M T=200°) Results were as follows:

    ______________________________________                                         ##STR11##                                                                     ##STR12##                                                                    Time                                                                          ______________________________________                                        11/2 hours 20%    66%     7%                                                  21/2 hours 21%    61%    11%                                                  41/4 hours 22%    51%    20%                                                  61/2 hours 23%    42%    26%                                                  30 hours 22%      0      68%                                                  ______________________________________                                    

EXAMPLE 3

The reaction described in Example 1, 1st paragraph, was repeatedemploying various catalysts. The results are shown in the followingtable (for structures of compounds B and C--see Example 2).

    ______________________________________                                        Isomerisation of Compound B to Compound C using                               various Catalysts.                                                            Catalyst/Reaction  Reaction time                                                                            Percentage of                                   Conditions         (hours)    Compound C                                      ______________________________________                                        CH.sub.3 CO.sub.2 H, reflux                                                                      30         100                                             NaOAc, 5% Pd--C, EtOH, reflux                                                                    21.6       85.4                                            BF.sub.3 -Et.sub.2 O, dioxan, reflux                                                             24         83                                              PPA, 100°   1.5        76.sup.a                                        H.sub.3 PO.sub.4, H.sub.2 O, reflux                                                              21.6       25.1                                            ZnCl.sub.2, dioxan, reflux                                                                       30         22.5                                            (CH.sub.3 CO).sub.2 O, reflux                                                                    30         5                                               KOH, EtOH, 22°                                                                            30         5                                               ______________________________________                                         .sup.a Severe decomposition of compound C was observed after 2 hours.         PPA = Polyphosphoric acid                                                

EXAMPLE 4[8R*]-5,6,7,8-tetrahydro-8-([2S*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline.##STR13##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) and toluene(100 ml) was added 1.63 molar n-BuLi in hexane (93 ml) at -40° C. Theresulting anion solution was added to a mixture of phenylacetone (50 ml)and toluene (100 ml) at -40° C. The solution was allowed to warm to roomtemperature and the excess n-BuLi was quenched by adding 2N HCl (90 ml).The excess solvent was removed by evaporation. The resultant aqueousmixture was basified with saturated aqueous NaHCO₃ solution andextracted with EtOAc (3×100 ml). The extracts were dried (MgSO₄) and thesolvent removed by evaporation. The mixture of products was separated bychromatography[SiO₂ ; cyclohexane--CH₃ CO₂ CH₃ (4:1)]. Upon removal ofthe solvent by evaporation the product crystallised to give the titlecompound (2.25 g), m.p. 99°-101° C. (Found: C, 81.1; H, 8.1; N, 4.7.C.sub. 19 H₂₃ NO requires C, 81.1; H, 8.2; N, 5.0%).

EXAMPLE 5[8R*]-5,6,7,8-tetrahydro-8-([2R*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline##STR14##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) and toluene(100 ml) was added 1.63 molar n-BuLi in hexane (93 ml) at -40° C. Theresulting anion solution was added to a mixture of phenylacetone (50 ml)and toluene (100 ml) at -40° C. The resulting solution was allowed towarm to room temperature. The excess n-BuLi was quenched by adding2N-HCl (90 ml). The aqueous layer was separated, basified with saturatedaqueous NaHCO₃ solution, and extracted with Et₂ O (3×100 ml). Theethereal extracts were dried (MgSO₄) and the solvent removed byevaporation. The mixture of products was separated by chromatography[SiO₂ ; cyclohexane--methyl acetate (80:20)]. The solvent was removed byevaporation and the residue dissolved in Et₂ O, to which an etherealsolution of HCl (50 ml) was added. The precipitate was collected byfiltration, washed with Et₂ O, and dried in vacuo to give the titlecompound as a hydrochloride 11/2 hydrate (2.09 g) m.p. 98°-100° C.(Found: C, 66.2; H, 7.5; N, 3.9. C₁₉ H₂₃ NO.HCl.3/2H₂ O requires C,66.2; H, 7.9; N, 4.1%).

EXAMPLE 6 5,6,7,8-tetrahydro-8-(1-hydroxyethyl)-3-methylquinoline##STR15##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) and dry THF(150 ml) was added 1.63 molar n-BuLi in hexane (108 ml) at -30° C. Theresulting anion solution was added to a solution of acetaldehyde (50 ml)in anhydrous THF (50 ml) at -30° C. The solution was allowed to warm toroom temperature. The excess n-BuLi was quenched with 2N-HCl (20 ml).The excess acetaldehyde and solvent were removed by evaporation. Theresultant aqueous mixture was basified with saturated aqueous NaHCO₃solution and extracted with Et₂ O (3×100 ml). The ethereal extracts weredried (MgSO₄) and the solvent removed by evaporation. The mixture ofproducts was separated by chromatography (SiO₂ ; EtOAc). The solvent wasremoved by evaporation and the residue dissolved in Et₂ O to whichethereal HCl (50 ml) was added. The product was removed by filtration,washed with Et₂ O and dried in vacuo to give the title compound as thehydrochloride 1/4 hydrate (1.13 g) m.p. 172°-175° C. (Found: C, 62.4; H,7.9; N, 6.0 C₁₂ H₁₇ NO.HCl.1/4H₂ O requires C, 62.1; N, 8.0; N, 6.0%).

EXAMPLE 7 5,6,7,8-Tetrahydro-8-(2(2-hydroxy)propyl)-3-methylquinoline##STR16##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (23.44 g, 159 mmol)and toluene (200 ml) was added 1.63 molar n-BuLi in hexane (108 ml) at-40°. After 15 mins. the resulting anion solutio was added to a solutionof acetone (100 ml) in toluene (200 ml). The solution was allowed towarm to room temperature and was treated with 2N-HCl (90 ml). The excessacetone was removed by evaporation in vacuo. The resultant aqueousmixture was basified with saturated aqueous NaHCO₃ solution andextracted into Et₂ O (3×100 ml). The ethereal extracts were dried(MgSO₄) and the solvent removed by evaporation in vacuo. The mixture ofproducts were separated by chromotography [SiO₂ ; EtOAc-petrol (1:4)] togive the free base (7.303 g, 22%) of the title compound as a red oil.

A small quantity of the free base (0.744 g) was dissolved in Et₂ O andtreated with ethereal HCl. The product was removed by filtration, washedwith Et₂ O, and dried in vacuo to give the title compound as thehydrochloride, m.p. 140°-144°. (Found: C, 63.2; H, 8.3; N, 5.5. C₁₃ H₁₉NO.HCl.1/4H₂ O requires C, 63.4; H, 8.4; N, 5.7%).

EXAMPLE 8 5,6,7,8-Tetrahydro-3-methyl-8-(2-propylidene)quinoline##STR17## Experimental Details

A mixture of 5,6,7,8-tetrahydro-8-(2(2-hydroxy)propyl)-3-methylquinoline(3.044 g, 14.8 mmol) and polyphosphoric acid (20 g) was vigorouslystirred at 80°-90° for 50 mins. and then poured into saturated aqueousNa₂ CO₃ solution (200 ml). The aqueous solution was extracted with Et₂ O(2×100 ml) and the ethereal extracts dried (MgSO₄) and evaporated invacuo to give an oil. Purification by column chromatography [SiO₂ ;hexane-propan-2-ol(1:1)] and bulb-to-bulb distillation gave the titlecompound (1.855 g, 67%) as a colourless oil, b.p. 150°-5°/0.1 mm Hg(Found: C, 83.25; H, 9.3; N, 7.5 C₁₃ H₁₇ N requires C, 83.4; H, 9.15; N,7.5%).

We claim:
 1. A compound of formula III ##STR18## or a pharmaceuticallyacceptable salt thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are,independently, hydrogen, alkyl of 1 to 6 carbon atoms cycloalkyl of 4 to6 carbon atoms, aralkyl of 7 to 12 carbon atoms or phenyl, any of whichcyclic structures may be monosubstituted by alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, or --CF₃ ; or R² and R³, takentogether, form a 5, 6 or 7 membered saturated carbocyclic ring; R⁴ andR⁵ may also be alkoxy of 1 to 6 carbon atoms or cycloalkoxy of 4 to 6carbon atoms; n is one of the integers 1, 2 or 3; and, if more than oneR⁴ group is present, the R⁴ groups may be the same or different; andcarboxylic acid esters of the depicted hydroxy substituent; with theprovisos that (1) when R¹, R², R³, R⁴, and R⁵ are all hydrogen, R⁶ andR⁷ are other than hydrogen, and (2) when R⁴ is methyl, R⁶ and R⁷ are notboth methyl.
 2. A compound of formula III as claimed in claim 1, whereinn is 2 and R¹, R², R³, R⁴ and R⁵ selected from hydrogen and alkyl of 1to 6 carbon atoms.
 3. A compound of formula IIIA ##STR19## or apharmaceutically acceptable acid addition salt thereof wherein R¹⁰ isalkyl of 1 to 6 carbon atoms and R⁶ and R⁷ are selected from hydrogen,alkyl of 1 to 6 carbon atoms, cycloalkyl, or aralkyl of 7 to 12 carbonatoms. 4.[8R*]-5,6,7,8-tetrahydro-8-([2S*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline,the 2R* isomer thereof, or a pharmaceutically acceptable acid additionsalt thereof. 5.5,6,7,8-Tetrahydro-8-(2(2-hydroxy)propyl-3-methylquinoline or an acidaddition salt thereof.